Combination of Insulin-like Growth Factor-1 Receptor (IGF1R) or Insulin Receptor Inhibitors with Immune Checkpoint Inhibitors in Management of Triple-Negative Breast Cancer (UCLA Case No. 2020-872)

UCLA researchers in the Department Joe C. Wen School of Nursing have developed a novel targeted therapy for triple-negative breast cancer with a potential synergy with immunotherapy.

BACKGROUND: Triple-negative breast cancer (TNBC) accounts for about 10-15% of women with breast cancer (BC), but its mortality rate is disproportionally high, causing almost 50% of all BC deaths. By definition, TNBC tumors lacks notable biomarkers to target and shows significant heterogeneity, hindering the development of effective targeted therapies. These characteristics, as well as an overall poor understanding of the mechanism behind progression, results in TNBC being a devastating disease for women across all age groups. Currently, the standard of treatment for TNBC is the use of small molecule chemotherapeutics. Unfortunately, these therapeutics are only effective for for a small subset of TBNC patients and are hindered by significant side effects. Cancer immunotherapy, such as immune checkpoint inhibition (ICI), is an emerging first-line therapy in oncology; however, response rates in TNBC remain below 20-30%, leaving the majority of patients without effective options. This highlights the need for targeted therapies that can enhance ICI efficacy and provide more durable responses.

INNOVATION: UCLA researchers have identified insulin-like growth factor receptor (IGF1R) and insulin receptor (IR) as novel therapeutic targets for TNBC, potentially enabling a more targeted and less cytotoxic therapeutic regimen for TNBC patients. In preclinical mouse models, dual inhibition of IGF1R/IR using a particular antagonist suppressed TNBC progression, whereas targeting IGF1R alone was ineffective in prior clinical trials. Furthermore, IGF1R/IR co-inhibition was shown to modulate specific immune activities to enhance antitumor immune reactions. In addition, researchers found that IGF1R/IR inhibition alters the biology of small extracellular vesicles (sEV). Treatment with the IGF1R/IR antagonist increased sEV-associated proteins and IGF-binding proteins, while reducing the bioavailability of IGF2, a pro-survival ligand commonly overexpressed in TNBC.  These changes promote apoptosis and reduce tumor survival. Together, these findings position dual IGF1R/IR inhibition as a mechanism to not only suppress tumor growth, but also to shape the tumor immune and extracellular vesicle environment to improve immunotherapy outcomes. 

Potential Applications: 

• Combinational therapies for TNBC treatment
• IGF2 as a novel biomarker of TNBC and treatment response
• sEV-based diagnostics to monitor treatment response

Advantages:

• Reduction of tumor growth and migration when co-targeting IFG1R and IR
• Synergy with existing ICI treatments
• IGF1R/IR antagonists already available from multiple pharmaceutical companies

Development to date: Efficacy of IGF1R/IR co-inhibition with or without ICI has been shown in cell culture and mouse models. High expression of IGF2 is observed in archival breast samples of TNBC patients. A US patent application has been filed.

Related Papers (by the inventors only): 

• Hamilton, N., Austin D, Márquez-Garbán D., Sanchez R, Chau B, Foos K, Wu Y, Vadgama J, Pietras R. (2017) Receptors for Insulin-Like Growth Factor-2 and Androgens as Therapeutic Targets in Triple-Negative Breast Cancer. Int J Mol Sci. Nov 2:18(11). pii: E2305. doi: 10.3390/ijms18112305.
• Hamilton, N., Márquez-Garbán D., Rogers, B., Austin, D., Foos, K., Tong, A., Adams, D., Vadgama, J., Brecht, M.L. & Pietras, R. (2019) Insulin-Like Growth Factor-I Receptor/Insulin Receptor (IGF1R/IR) and Androgen Receptor (AR) Antagonist Combinations Inhibit Triple-Negative Breast Cancer Cell Migration. SPG BioMed. doi: .org/10.32392/biomed.69

Keywords: TNBC, triple-negative breast cancer, immune checkpoint inhibitors, immunotherapy, IGF1R, IR insulin receptor, IGF2, endocrinology, oncology, PD-1, PD-L1, women’s health, therapeutics, biomarker, small extracellular vesicles